Research: The research goal of our laboratory is to understand the molecular mechanism of tumor necrosis factor (TNF) signaling and the regulation of cell death and the role of inflammation in tumorigenesis. Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a critical role in diverse cellular events, including cell proliferation, differentiation, and apoptosis. TNF is also involved in many types of diseases, including cancer. Inappropriate production of TNF plays a critical role in the pathogenesis of both acute and chronic inflammatory diseases such as septic shock, acquired immunodeficiency syndrome (AIDS), and arthritis. The development of anti-TNFalpha therapy is arguably the most significant achievement in the treatment of autoimmune-diseases, such as rheumatoid arthritis and Crohn's disease. Opposing effects of TNF on cancer have been described: a high dose of TNF (acute inflammation) has anti-neoplastic effects, such as direct cytotoxicity on certain types of cancer, while an endogenous low-dose of TNF (chronic inflammation) promotes cancer development. Studies from many laboratories have demonstrated that the diverse TNF-mediated biological responses are achieved through activating multiple signaling pathways (see below). Although much information about TNF signaling has been obtained in recent years, many molecular aspects of TNF signaling remain unknown. Especially, for a given type of cells, we still do not understand how cells choose between life and death after TNF treatment. Therefore, uncovering the molecular mechanism for the regulation of TNF signaling will not only shed new light on the physiological regulation of TNF function but also help to maximize the potential of applying or blocking this cytokine in cancer treatment. In the last 5 years, we have made several significant contributions to the understanding of the molecular mechanism for the regulation of TNF signaling. Most recently, we generated tumor necrosis factor receptor 1-associated death domain protein (TRADD) null mice and were able to demonstrate the important role of TRADD in TNF receptor 1 (TNFR1) signaling. In the next 4 years, we will continue to investigate the regulation of TNF signaling, particularly the molecular mechanisms that underlie the life and death decision of cells in response to TNF. Therefore, we will focus our research on the following two areas: 1) studying the regulation of TNF-induced apoptosis by the novel anti-apoptotic protein, ATIA, and its potential role in tumorigenesis;2) investigating the role of TRADD in death receptor signaling and the importance of TRADD-mediated inflammatory responses during tumorigenesis. We believe that these proposed studies will provide new knowledge about the underlying molecular events that determine the outcome of a cell exposed to TNF and other death factors and this may eventually lead to improving the therapeutic value of these death factors. In addition, these studies will shed new light on the tumor-promoting effect of inflammatory responses and may help to develop novel cancer treatments. More recently, we found that ATIA is regulated by HIF-1 and protects cells from hypoxia-induced apoptosis.